The invention pertains to a process for preparing guaifenesin tannate.
Guaifenesin is a well-known commercially available compound. It is frequently referred to as guaiphenesin or glyceryl guiacolate. Its chemical name is 3-(2-methoxyphenoxy)-1,2-propanediol. It is a solid having a melting point of 78.5xc2x0 C, and its molecular formula is C10H14O4.It is only slightly soluble (i.e, about 5 wt. %) in water, but is readily soluble in alcohols such as methanol, ethanol, isopropanol, etc. By way of further identification, its CAS number is 93-14-1.
Guaifenesin finds its principal use as an expectorant for promoting or facilitating the removal of secretions from the respiratory tract in a warm-blooded animal, principally a human being. It helps to loosen phlegm (mucus) and thin bronchial secretions to rid the bronchial passageways of bothersome mucus, drain bronchial tubes and makes coughs more productive. It is typically administered to human beings in need of such medication in the form of tablets and/or suspensions.
Guaifenesin has also proven useful as a central nervous system muscle relaxant for non-human warm-blooded animals, particularly horses and cattle. For animals in need of a muscle relaxant, guaifenesin is typically administered in injectable form.
In recent years, research has indicated that guaifenesin may be useful for alleviation of the symptoms of fibromyalgia syndrome and chronic fatigue syndrome. If such research proves that guaifenesin does in fact alleviate the symptoms of FMS and CFS, it will be a very welcome adjunct in the treatment of these syndromes which are quite painful.
In contradistinction to the antihistamines of which many are unstable in the form of their free bases, guaifenesin is relatively stable. Therefore, little, if any attention, has been paid in recent years to improving guaifenesin compositions. On the other hand, there is a considerable amount of prior art which has emerged in recent years which has been directed to salts of antihistamines, principally tannate salts, which stabilize the antihistamine bases. For example, see U.S. Patents 5,599,846; 5,663,415; 6,037,358; 6,287,597; and 6,306,904.
Tannic acid is commercially available and is used in many industrial applications. It is frequently referred to as gallotannic acid, gallotannin; glycerite or tannin. It is a pale tan powder having a decomposition point of 210-215xc2x0 C., and is highly soluble in water and alcohols. Its molecular formula is C76H52O46 and its CAS number is 1401-55-4. Tannic acid is typically produced from Turkish or Chinese nutgall and has a complex non-uniform chemistry and typically contains about 5-10 wt. % water.
As mentioned above, guaifenesin, in contradistinction to the antihistamines, is quite stable and therefore would not require the addition of a material such as tannic acid to render it stable. However, guaifenesin does have one drawback: it is readily absorbed in the patient""s body, but its action is relatively short-lived. Indeed, its plasma half-life is only one hour. Accordingly, while it provides relatively quick relief to the patient, the patient is required to take relatively high doses several times a day until the condition which necessitated the administration of the guaifenesin has been alleviated. This presents a particular problem to the patient suffering from chronic bronchitis who is therefore required to be on a constant regimen of guaifenesin, thereby increasing the likelihood of the occurrence of undesirable side effects.
It would be very desirable if a form of guaifenesin was available which would have extended-release properties, i.e., the guaifenesin would be slowly released into the patient""s bloodstream over a prolonged period of time. Thus far, the only slow-release forms of guaifenesin which are available are those such as polymer coated tablets. Such prior art formulations provide mixed results in that the guaifenesin is not available for adsorption into the patient""s bloodstream until the polymeric coating has been dissolved, but thereafter the guaifenesin is quickly absorbed and metabolized. The result is that frequently, the guaifenesin must again be administered to the patient within the period of only a few hours.
Commercially available antihistamine tannate compositions are relatively impure. Such compositions are typically prepared by reacting the antihistamine free base with tannic acid in the presence of a volatile solvent, usually isopropanol. The yield is only fair (e.g. about 70%) and decomposition products e.g. 2-5 wt. %, and a significant amount of the volatile solvent, e.g. 6-10 wt. %, based on the weight of the composition, remains with the product and cannot be removed.
U.S. Patent 5,663,415 discloses a process for preparing antihistamine tannates which involves the reaction between the antihistamine free base and tannic acid in aqueous media to form an aqueous solution of the antihistamine tannate. Since the resultant antihistamine tannate is generally heat sensitive, the antihistamine tannate is recovered from the aqueous solution by freeze-drying. The process disclosed in the xe2x80x98415 patent results in a pure product in which the only residual impurity is water in the amount of less than 10 wt. %
However, guaifenesin is not an antihistamine and accordingly it does not contain a nitrogen atom which would result in a reaction to produce a tannate salt. Guaifenesin is a diol and it would have been expected that it could react with tannic acid to form a new composition. It has been surprisingly found that guaifenesin tannate can be prepared by the process of the present invention and that the guaifenesin tannate is not a salt, but rather is believed to be a complex.